Developmental Differences in the Accumbal Dopaminergic Response to Repeated Ethanol Exposure

Abstract

Recent research indicates that alcohol use/abuse is often initiated during the adolescent period and that brain reinforcement pathways (e.g., the mesolimbic dopamine [DA] pathway) are undergoing developmental transition. Our research focuses on the effects of ethanol administration on neural mechanisms associated with addiction in preadolescent (postnatal day [PND] 25), adolescent (PND 35, PND 45), and young adult (PND 60) animals. Using conditioned place preference (CPP) testing, we have shown that adolescent animals are unique in their responses to ethanol. Since CPP has been associated with contextually conditioned incentive motivation, our results suggest that younger animals may be more vulnerable to addiction. The present data reveal that adolescent animals are neurochemically distinct in response to ethanol's effects. Using in vivo microdialysis within the nucleus accumbens septi (NAcc), we have determined the DAergic response across development. Results reveal that basal levels of DA transition during the adolescent period and differ from preadolescent or adult animals. Specifically, PND 45 animals exhibited significantly higher, and PND 25 significantly lower, basal DA levels than all other ages examined. Further, repeated exposure to ethanol elevated basal DA levels significantly regardless of age or dose. Basal 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio also differed as a function of age, with PND 35 and PND 60 animals demonstrating the highest ratios, and PND 45 animals producing the lowest baseline levels. Repeated ethanol exposure produced significant changes in basal ratios as a function of age. Interestingly, PND 45 animals exhibited no change in ratios with repeated exposure, while all other ages demonstrated a dose-dependent rise in DOPAC/DA ratios. These data indicate an age-dependent difference in the homeostatic alterations of mesolimbic systems in response to repeated ethanol treatment, an effect that may manifest itself as differences in behavioral responsivity and conditionability to the drug and the drug's effects.

Cocaine during adolescence enhances dopamine in response to a natural reinforcer

“…Specifically, rats pretreated with cocaine as adults had lower baseline DA levels than saline pretreated rats. Basal DA levels (nM concentrations) reported here are consistent with others [6,52,55] however, some report lower levels such as pM [68,77] and fM [13,24,35] concentrations. The decreases observed in basal DA after cocaine administration and withdrawal in the present study are consistent with other studies in the adult literature [39,51,66].…”

Neural Development in Adolescence

“…Consequently, such experiences might acquire a special character because the adolescents might repeat them several times. This hypothesis seems to agree with some findings reported in the literature that show that DA release in the reward system in adolescent rats is greater when they are exposed to new situations [36] or given cocaine [37], methamphetamine [38], or alcohol [39,40].…”

Alcohol during adolescence selectively alters immediate and long-term behavior and neurochemistry

“…The concentration that reached steady state (DA in = DA out) was considered the basal level. Both approaches yielded similar age results, with late adolescent animals (PND 45) having significantly higher basal DA levels than adults, but with the conventional method (Philpot and Kirstein, 2004), dialysate DA levels obtained in adolescents were higher than those obtained using the quantitative method (Figure 4; Badanich et al, 2006). Additionally, the quantitative approach revealed lower basal DA levels for early adolescent (PND 35) rats.…”

“…Preadolescent (PND 25), early adolescent (PND 35), late adolescent (PND 45) and young adult (PND 60) rats were implanted with cannula and microdialysis probes into the NAcc. Using the conventional approach, artificial cerebrospinal fluid was perfused through the probe and DA was recovered (Philpot and Kirstein, 2004). Using the quantitative approach (adopted from Olson & Justice, 1993) differing concentrations of DA were perfused and the dialysate analyzed to determine levels based on the concentration put in and the concentration recovered (Badanich, Adler and Kirstein, 2006).…”